Pancreatic neuroendocrine tumor progression and resistance to everolimus: the crucial role of NF-kB and STAT3 interplay.
Everolimus
NF-kB
Pancreatic neuroendocrine tumors
Resistance
STAT3
Journal
Journal of endocrinological investigation
ISSN: 1720-8386
Titre abrégé: J Endocrinol Invest
Pays: Italy
ID NLM: 7806594
Informations de publication
Date de publication:
26 Oct 2023
26 Oct 2023
Historique:
received:
08
09
2023
accepted:
09
10
2023
medline:
26
10
2023
pubmed:
26
10
2023
entrez:
26
10
2023
Statut:
aheadofprint
Résumé
The finding of mTOR overactivation in patients affected by pancreatic neuroendocrine tumors (Pa-NETs) led to their treatment with the mTOR inhibitor everolimus. Unfortunately, the efficacy of everolimus is restricted by the occurrence of resistance. The mechanisms leading to Pa-NETs' progression and resistance are not well understood. Notably, chronic inflammation is implicated in NET development. NF-kB is involved in inflammation and drug resistance mechanisms through the activation of several mediators, including STAT3. In this respect, NF-κB and STAT3 interaction is implicated in the crosstalk between inflammatory and tumor cells. We investigated the expression of NF-kB in different Pa-NETs by RT-qPCR and immunohistochemistry. Then, we studied the role of NF-κB and STAT3 interplay in QGP-1 cells. Subsequently, we assessed the impact of NF-κB and STAT3 inhibitors in QGP-1 cell proliferation and spheroids growth. Finally, we evaluated the implication of the NF-kB pathway in everolimus-resistant Pa-NET cells. We found that the increased NF-kB expression correlates with a higher grade in Pa-NETs. The activation of the STAT3 pathway induced by TNFα is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells. Interestingly, we found that NF-kB, STAT3, IL-8, and SOCS3 are overexpressed in QGP-1R compared to QGP-1. Since the NF-kB pathway is implicated in Pa-NETs' progression and resistance to everolimus, these data could explain the potential use of NF-kB as a novel therapeutic target in Pa-NET patients.
Identifiants
pubmed: 37882947
doi: 10.1007/s40618-023-02221-1
pii: 10.1007/s40618-023-02221-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : PRIN 2022CZR88M
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : P20227KXJK
Informations de copyright
© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).
Références
Dasari A, Shen C, Halperin D et al (2017) Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 3:1335–1342. https://doi.org/10.1001/jamaoncol.2017.0589
doi: 10.1001/jamaoncol.2017.0589
pubmed: 28448665
pmcid: 5824320
Nagtegaal ID, Odze RD, Klimstra D et al (2020) The 2019 WHO classification of tumours of the digestive system. Histopathology 76:182–188. https://doi.org/10.1111/his.13975
doi: 10.1111/his.13975
pubmed: 31433515
Pavel M, O’Toole D, Costa F et al (2016) ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 103:172–185
doi: 10.1159/000443167
pubmed: 26731013
Missiaglia E, Dalai I, Barbi S et al (2010) Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 28:245–255. https://doi.org/10.1200/JCO.2008.21.5988
doi: 10.1200/JCO.2008.21.5988
pubmed: 19917848
Zhou CF, Ji J, Yuan F et al (2011) mTOR activation in well differentiated pancreatic neuroendocrine tumors: a retrospective study on 34 cases. Hepatogastroenterology 58:2140–2143. https://doi.org/10.5754/hge11212
doi: 10.5754/hge11212
pubmed: 22024086
Yao JC, Shah MH, Ito T et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors for the RAD001 in advanced neuroendocrine tumors, third trial (RADIANT-3) study group. N Engl J Med 364:514–523. https://doi.org/10.1056/NEJMoa1009290
doi: 10.1056/NEJMoa1009290
pubmed: 21306238
pmcid: 4208619
Yao JJC, Fazio N, Singh S et al (2016) Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387:968–977. https://doi.org/10.1016/S0140-6736(15)00817-X
doi: 10.1016/S0140-6736(15)00817-X
pubmed: 26703889
Vandamme T, Beyens M, De Beeck KO et al (2016) Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors. Br J Cancer 114:650–658. https://doi.org/10.1038/bjc.2016.25
doi: 10.1038/bjc.2016.25
pubmed: 26978006
pmcid: 4800296
Berkovic MC, Cacev T, Ivkovic TC et al (2014) New insights into the role of chronic inflammation and cytokines in the etiopathogenesis of gastroenteropancreatic neuroendocrine tumors. Neuroendocrinology 99:75–84. https://doi.org/10.1159/000362339
doi: 10.1159/000362339
Vitale G, Carra S, Ferraù F et al (2020) Gastroenteropancreatic neuroendocrine neoplasms and inflammation: a complex cross-talk with relevant clinical implications. Crit Rev Oncol Hematol 146:102840
doi: 10.1016/j.critrevonc.2019.102840
pubmed: 31918344
Vitale G, Dicitore A, Barrea L et al (2021) From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: are we on the highway to hell? Rev Endocr Metab Disord 22:511–525. https://doi.org/10.1007/s11154-020-09589-y
doi: 10.1007/s11154-020-09589-y
pubmed: 32935263
Temiz-resitoglu M, Sinem D, Cecen P (2017) Activation of mTOR/IκB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats. Eur J Pharmacol 802:7–19. https://doi.org/10.1016/j.ejphar.2017.02.034
doi: 10.1016/j.ejphar.2017.02.034
pubmed: 28228357
Kunsch C, Lang RK, Rosen CA, Shannon MF (1994) Synergistic transcriptional activation of the IL-8 gene by NF-kappa B p65 (RelA) and NF-IL-6. J Immunol 153:153–164. https://doi.org/10.4049/jimmunol.153.1.153
doi: 10.4049/jimmunol.153.1.153
pubmed: 8207232
Hussain F, Wang J, Ahmed R et al (2010) Cytokine The expression of IL-8 and IL-8 receptors in pancreatic adenocarcinomas and pancreatic neuroendocrine tumours. Cytokine 49:134–140. https://doi.org/10.1016/j.cyto.2009.11.010
doi: 10.1016/j.cyto.2009.11.010
pubmed: 20005738
Braeuer SJ, Büneker C, Mohr A, Zwacka RM (2006) Constitutively activated nuclear factor-κB, but not induced NF-κB, leads to TRAIL resistance by up-regulation of X-linked inhibitor of apoptosis protein in human cancer cells. Mol Cancer Res. https://doi.org/10.1158/1541-7786.MCR-05-0231
doi: 10.1158/1541-7786.MCR-05-0231
pubmed: 17050666
Taniguchi K, Karin M (2018) REVIEWS NF-κB, inflammation, immunity and cancer : coming of age. Nat Publ Gr 18:309–324. https://doi.org/10.1038/nri.2017.142
doi: 10.1038/nri.2017.142
Lopez-aguiar AG, Postlewait LM, Ethun CG et al (2019) STAT3 inhibition for gastroenteropancreatic neuroendocrine tumors : potential for a new therapeutic target? J Gastrointest Surg 24:1138–1148
doi: 10.1007/s11605-019-04261-6
pubmed: 31144189
Ghosh S, Karin M (2002) Missing pieces in the NF-κB puzzle. Cell 109:S81–S96
doi: 10.1016/S0092-8674(02)00703-1
pubmed: 11983155
Bassères DS, Baldwin AS (2006) Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression. Oncogene 25:6817–6830
doi: 10.1038/sj.onc.1209942
pubmed: 17072330
Gilmore TD (2003) The Re1/NF-kappa B/I kappa B signal transduction pathway and cancer. Cancer Treat Res 115:241–265
doi: 10.1007/0-306-48158-8_10
pubmed: 12613200
Grivennikov SI, Karin M (2010) Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21:11–19. https://doi.org/10.1016/j.cytogfr.2009.11.005
doi: 10.1016/j.cytogfr.2009.11.005
pubmed: 20018552
Kubo M, Hanada T, Yoshimura A (2003) Suppressors of cytokine signaling and immunity. Nat Immunol 4:1169–1176
doi: 10.1038/ni1012
pubmed: 14639467
Bromberg JF, Wrzeszczynska MH, Devgan G et al (1999) Stat3 as an oncogene. Cell 98:295–303. https://doi.org/10.1016/S0092-8674(00)81959-5
doi: 10.1016/S0092-8674(00)81959-5
pubmed: 10458605
Yu H, Jove R (2004) The stats of cancer—new molecular targets come of age. Nat Rev Cancer 4:97–105
doi: 10.1038/nrc1275
pubmed: 14964307
Sansone P, Storci G, Tavolari S et al (2007) IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117:3988–4002. https://doi.org/10.1172/JCI32533
doi: 10.1172/JCI32533
pubmed: 18060036
pmcid: 2096439
Yin YZ, Wang YC (2006) Analysis of behaviour of steel beams with web openings at elevated temperatures. Steel Compos Struct 6:15–31. https://doi.org/10.1186/1476-4598-5-15
doi: 10.1186/1476-4598-5-15
Kesanakurti D, Chetty C, Rajasekhar Maddirela D et al (2013) Essential role of cooperative NF-κB and Stat3 recruitment to ICAM-1 intronic consensus elements in the regulation of radiation-induced invasion and migration in glioma. Oncogene 32:5144–5155. https://doi.org/10.1038/onc.2012.546
doi: 10.1038/onc.2012.546
pubmed: 23178493
Fan Y, Mao R, Yang J (2013) NF- κ B and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 4:176–185. https://doi.org/10.1007/s13238-013-2084-3
doi: 10.1007/s13238-013-2084-3
pubmed: 23483479
pmcid: 4875500
Vitali E, Boemi I, Piccini S et al (2020) A novel insight into the anticancer mechanism of metformin in pancreatic neuroendocrine tumor cells. Mol Cell Endocrinol 509:110803. https://doi.org/10.1016/j.mce.2020.110803
doi: 10.1016/j.mce.2020.110803
pubmed: 32251713
Vitali E, Cambiaghi V, Zerbi A et al (2016) Filamin-a is required to mediate SST2 effects in pancreatic neuroendocrine tumours. Endocr Relat Cancer 23:181–190. https://doi.org/10.1530/ERC-15-0358
doi: 10.1530/ERC-15-0358
pubmed: 26733502
Vitali E, Boemi I, Rosso L et al (2017) FLNA is implicated in pulmonary neuroendocrine tumors aggressiveness and progression. Oncotarget 8:77330–77340. https://doi.org/10.18632/oncotarget.20473
doi: 10.18632/oncotarget.20473
pubmed: 29100390
pmcid: 5652783
Vitali E, Boemi I, Tarantola G et al (2020) Metformin and everolimus: a promising combination for neuroendocrine tumors treatment. Cancers (Basel) 12:1–18. https://doi.org/10.3390/cancers12082143
doi: 10.3390/cancers12082143
Lania AG, Mantovani G, Ferrero S et al (2004) Proliferation of transformed somatotroph cells related to low or absent expression of protein kinase A regulatory subunit 1A protein. Cancer Res 64:9193–9198. https://doi.org/10.1158/0008-5472.CAN-04-1847
doi: 10.1158/0008-5472.CAN-04-1847
pubmed: 15604292
Herrera-Martínez AD, van den Dungen R, Dogan-Oruc F et al (2019) Effects of novel somatostatin-dopamine chimeric drugs in 2D and 3D cell culture models of neuroendocrine tumors. Endocr Relat Cancer 26:585–599. https://doi.org/10.1530/ERC-19-0086
doi: 10.1530/ERC-19-0086
pubmed: 30939452
Raj N, Reidy-Lagunes D (2016) Systemic therapies for advanced pancreatic neuroendocrine tumors. Hematol Oncol Clin North Am 30:119–133
doi: 10.1016/j.hoc.2015.09.005
pubmed: 26614372
Lee L, Ito T, Jensen RT (2018) Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence. Expert Opin Pharmacother 19:909–928. https://doi.org/10.1080/14656566.2018.1476492
doi: 10.1080/14656566.2018.1476492
pubmed: 29757017
pmcid: 6064188
O’Reilly KE, Rojo F, She QB et al (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508. https://doi.org/10.1158/0008-5472.CAN-05-2925
doi: 10.1158/0008-5472.CAN-05-2925
pubmed: 16452206
pmcid: 3193604
Mahečić DH, Berković MC, Zjačić-Rotkvić V et al (2020) Inflammation-related cytokines and their roles in gastroenteropancreatic neuroendocrine neoplasms. Bosn J Basic Med Sci 20:445–450. https://doi.org/10.17305/bjbms.2020.4471
doi: 10.17305/bjbms.2020.4471
pmcid: 7664780
Waugh DJJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14:6735–6741
doi: 10.1158/1078-0432.CCR-07-4843
pubmed: 18980965
Elliott CL, Allport VC, Loudon JAZ et al (2001) Nuclear factor-kappa B is essential for up-regulation of interleukin-8 expression in human amnion and cervical epithelial cells. Mol Hum Reprod 7:787–790. https://doi.org/10.1093/molehr/7.8.787
doi: 10.1093/molehr/7.8.787
pubmed: 11470867
Taniguchi K, Karin M (2018) NF-B, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 18:309–324
doi: 10.1038/nri.2017.142
pubmed: 29379212
Bai D, Ueno L, Vogt PK (2009) Akt-mediated regulation of NFκB and the essentialness of NFκB for the oncogenicity of PI3K and Akt. Int J Cancer 125:2863–2870. https://doi.org/10.1002/ijc.24748
doi: 10.1002/ijc.24748
pubmed: 19609947
pmcid: 2767458
El Jamal SM, Yaseen AA, Alatassi H et al (2017) Strong NFkB expression is associated with high-grade dysplasia in Barrett’s esophagus. Appl Immunohistochem Mol Morphol 25:329–333. https://doi.org/10.1097/PAI.0000000000000359
doi: 10.1097/PAI.0000000000000359
pubmed: 26990751
Sarkar DK, Jana D, Patil PS et al (2013) Role of NF-κB as a prognostic marker in breast cancer: a pilot study in Indian patients. Indian J Surg Oncol 4:242–247. https://doi.org/10.1007/s13193-013-0234-y
doi: 10.1007/s13193-013-0234-y
pubmed: 24426730
pmcid: 3771050
Annunziata CM, Stavnes HT, Kleinberg L et al (2010) Nuclear factor κB transcription factors are coexpressed and convey a poor outcome in ovarian cancer. Cancer. https://doi.org/10.1002/cncr.25190
doi: 10.1002/cncr.25190
pubmed: 20564628
Inoue S, Ide H, Mizushima T et al (2018) Nuclear factor-kb promotes urothelial tumorigenesis and cancer progression via cooperation with androgen receptor signaling. Mol Cancer Ther 17:1303–1314. https://doi.org/10.1158/1535-7163.MCT-17-0786
doi: 10.1158/1535-7163.MCT-17-0786
pubmed: 29592878
Bakshi HA, Quinn GA, Nasef MM et al (2022) Crocin inhibits angiogenesis and metastasis in colon cancer via TNF-α/NF-kB/VEGF pathways. Cells 14:1–15. https://doi.org/10.3390/cells11091502
doi: 10.3390/cells11091502
Transl S, Author M, August PMC, et al (2022) CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression HHS public access. 14:1–33. https://doi.org/10.5281/zenodo.5797228
Fan Y, Mao R, Yang J (2013) NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 4:176–185
doi: 10.1007/s13238-013-2084-3
pubmed: 23483479
pmcid: 4875500
Burger M, Hartmann T, Burger JA, Schraufstatter I (2005) KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway. Oncogene 24:2067–2075. https://doi.org/10.1038/sj.onc.1208442
doi: 10.1038/sj.onc.1208442
pubmed: 15688008
Mcfarland BC, Hong SW, Rajbhandari R et al (2013) NF-κB-induced IL-6 ensures STAT3 activation and tumor aggressiveness in glioblastoma. PLoS ONE. https://doi.org/10.1371/journal.pone.0078728
doi: 10.1371/journal.pone.0078728
pubmed: 24278426
pmcid: 3835687
Chen H, Bian A, Yang FL et al (2021) Targeting STAT3 by a small molecule suppresses pancreatic cancer progression. Oncogene. https://doi.org/10.1038/s41388-020-01626-z
doi: 10.1038/s41388-020-01626-z
pubmed: 34862460
pmcid: 10184507
Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA (2009) Spheroid-based drug screen: considerations and practical approach. Nat Protoc 4:309–324. https://doi.org/10.1038/nprot.2008.226
doi: 10.1038/nprot.2008.226
pubmed: 19214182
Khongthong P, Roseweir AK, Edwards J (2019) The NF-KB pathway and endocrine therapy resistance in breast cancer. Endocr Relat Cancer 26:R369–R380. https://doi.org/10.1530/ERC-19-0087
doi: 10.1530/ERC-19-0087
pubmed: 32013374
Sciammarella C, Luce A, Riccardi F et al (2020) Lanreotide induces cytokine modulation in intestinal neuroendocrine tumors and overcomes resistance to everolimus. Front Oncol. https://doi.org/10.3389/fonc.2020.01047
doi: 10.3389/fonc.2020.01047
pubmed: 32766136
pmcid: 7379869